1. Field of the Invention
This invention relates to di-tert-butylhydroxyphenylthio derivatives which may be useful as medicine. More particularly, it relates to those intramolecularly having residues derived from saturated aliphatic acid, which inhibit the incorporation of LDL (Low Density Lipoprotein) by preventing the denaturation of LDL and are therefore useful as an anti-arteriosclerosis agent.
Beside, they have preventive activity to oxidation of lipid, ulcer formation, and lipoxygenase inhibitory actions based on their anti-oxidation activities and may be therefore useful as agent for vessel disorder, anti-ulcer agent, anti-inflammatory agent, anti-allergy agent, and the like.
2. Description of the Prior Art
Atherosclerosis is thought to occur in an initial but significant stage of arteriosclerosis, in such a manner that lipoid material mainly consisting cholesterol moves into the arterial wall to form foam cells accompanied by hyperplasia and consequent sclerosis. Atherosclerosis has been thought not to occur due to a single factor but accumulated factors over a long period of time, such as hypertension, hyperlipemia, excessive cigarette smoking, obesity, diabetes mellitus, hyperuricemia, stress, heredity, lack of exercise, etc. Among those factors, the behavior of cholesterol existing as LDL in blood is noted. What is especially important are penetration of LDL into the arterial wall and the incorporation of LDL into macrophages, and the subsequent accumulation of cholesterol at the wall and the vessel disorder. On the other hand, the following factors are considered to promote the occurrence of atherosclerosis: the increase of blood cholesterol due to the troubles on the incorporation of LDL into liver and the metabolism of LDL in liver, the hydrodynamic state of blood due to the change in the physical properties of red blood cell, etc., the damage of endothelium, the abnormal hyperplasia of the arterial wall and the depression of the lipid utilization in arterial tissues, and the like.
For the drug therapy of atherosclerosis, there have heretofore been used anti-arteriosclerosis agents such as pyridinol carbamate; lipid lowering agents such as chlofibrate, nicotinic acid, alpha-tyroxine and chloestyramine; and anti-platelet agents such as dipyridamole and aspirin, etc. Also, di-tert-butylphenol derivatives having anti-arteriosclerosis activity are disclosed in JP. Publication Nos. 77-27144, 85-39362, 77-125171, or the like. Further, structurally related compounds having anti-oxidative activity are disclosed in JP. Unexam. Publication Nos. 74-75551, 74-75552, 83-90545, 86-191670, 86-197554, 86-210073, 86-218570, 86-268664, 88-310820, 88-310821, U.S. Pat. No. 4,076,841 and Chemical Abstract (C.A.) Vol. 94, 30290c, 1981 and the like.
It is generally considered that normal LDL are not incorporated by reticuloenthelial cells (scavenger cells) such as macrophages and kupffer cells, but denaturated LDL are incorporated through a receptor thereto. Also, it is considered that even when a large amount of cholesterol is accumulated in cells, the receptor for denaturated LDL does not decrease in number in cells, so that the accumulation of cholesterol is unlimitedly enhanced whereby the conversion of reticuloenthelial cells into foam may take place resulting in establishment of arteriosclerosis.
According to the above consideration, atherosclerosis may be prevented by inhibiting the production of denatured LDL. Development of drugs which can inhibit the production of denatured LDL has thus been desired, but satisfaction is presently not obtained in this respect.